Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity

K. H. William Lau, David J. Baylink, Xiao Dong Zhou, Denise Rodriguez, Lynda Bonewald, Zihui Li, Davide Ruffoni, Ralph Müller, Chandrasekhar Kesavan, Matilda H C Sheng

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by crossbreeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (~1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocytederived IGF-I plays a key determining role in bone mechanosensitivity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number2
DOIs
StatePublished - Jul 15 2013
Externally publishedYes

Fingerprint

Osteocytes
Insulin-Like Growth Factor I
Bone and Bones
Knockout Mice
Up-Regulation
Tibia
Genetic Hybridization
Genes
Catenins
X-Ray Microtomography
Osteocalcin
Osteogenesis
Transgenic Mice

Keywords

  • Insulin-like growth factor I
  • Mechanical loading
  • Mechanotransduction
  • Osteocytes
  • Wnt

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. / William Lau, K. H.; Baylink, David J.; Zhou, Xiao Dong; Rodriguez, Denise; Bonewald, Lynda; Li, Zihui; Ruffoni, Davide; Müller, Ralph; Kesavan, Chandrasekhar; Sheng, Matilda H C.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 305, No. 2, 15.07.2013.

Research output: Contribution to journalArticle

William Lau, K. H. ; Baylink, David J. ; Zhou, Xiao Dong ; Rodriguez, Denise ; Bonewald, Lynda ; Li, Zihui ; Ruffoni, Davide ; Müller, Ralph ; Kesavan, Chandrasekhar ; Sheng, Matilda H C. / Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. In: American Journal of Physiology - Endocrinology and Metabolism. 2013 ; Vol. 305, No. 2.
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abstract = "This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by crossbreeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40{\%}) Sost expression in WT mice, but the loading not only did not reduce but upregulated (~1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocytederived IGF-I plays a key determining role in bone mechanosensitivity.",
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